Inorganic nanoparticles such as semiconductor quantum dots (QDs) and gold nanoparticles (AuNPs) are promising materials for use in an array of applications ranging from electronic devices,1,2 lasers,3,4 photovoltaic cells,5,6 analytical sensors,7,8 and biomedical imaging.9-13 Their promise stems from some of their unique physical and chemical properties that often exhibit size- and composition-dependence. For example, semiconductor nanocrystals such as those made of CdSe, CdS, and InAs cores have tunable size-dependent absorption, high extinction coefficients, and size-dependent Gaussian emission profiles, which are not easily obtainable with conventional organic fluorophores and fluorescent proteins;2,9,10,13 CdSe-based nanocrystals, in particular, exhibit remarkable resistance to chemical and photo-degradation.9,14,15 These features have generated a great interest for developing QDs as fluorescent platforms for use in biotechnology.9-16 Such platforms promise great advances in understanding a variety of biological processes, ranging from sensing to the tracking of intracellular protein movements and interactions.
To be successfully integrated in biotechnology, however, the nanoparticles should be robust, water dispersible, and exhibit long term stability over a wide range of physiological conditions. The nanoparticles should also be compatible with bio-conjugation techniques in order to allow straightforward and controllable coupling to biomolecules such as amino acids, peptides proteins, nucleic acids, and DNAs.
Three chemical approaches have been employed to synthesize luminescent QDs: 1) growth in inverse micelles (aqueous) carried at room tempertature,17,18 2) pyrolysis of organometallic precursors at high temperature and in coordinating solution,19-21 and 3) arrested precipitation carried out in aqueous solution using hydrophilic ligands such as thioglycolic acid.22,23 QDs grown at high temperature exhibit better physical characteristics; namely, a narrow size distribution, crystalline cores, and superior optical and spectroscopic properties, including high fluorescence quantum yields.19-21,24-26 
Unfortunately, however, the QDs made using these techniques are coated with hydrophobic ligands, making them dispersible only in organic solutions. In order to render these coated QDs water dispersible and, thereby compatible with physiological conditions the coating must subsequently be modified, adding an undesirable extra step to complicate the process.
Gold nanoparticles are often prepared using the classic citrate reduction of aurate pioneered by Turkevich and Frens.27-28 This synthetic route provides citrate-stabilized nanoparticles. Like the QDs, in order to render these gold nanoparticles water dispersible, their coatings must be modified with hydrophilic ligands if further conjugation to biomolecules is desired.
Several strategies for rendering QDs water dispersible have previously been developed. These strategies include silica coating,29-31 encapsulation within amphiphilic polymers and lipid micelles,32-38 and exchanging the native hydrophobic coating with hydrophilic organic ligands.39-43 The latter strategy, called “cap exchange,” is widely used because it is relatively easy to implement, and it tends to produce compact nanorcyrtals39-42 having a small hydrodynamic size.
Regardless of the strategy used, hydrophilic nanocrystals preferably have a few key properties, including: colloidal stability over a broad range of buffers and in biological media and compatibility with easy to implement bio-conjugation techniques. The compatibility with easy to implement bio-conjugation techniques allows for specific biomolecules (e.g., peptides and proteins) to be attached to the nanocrystal surfaces to form functional platforms that can be used for developing nanoparticle-based sensing, imaging, and in vivo tracking materials.
For the cap exchange strategy, the stability of the nanocrystals is determined by the nature of the capping ligand (coating) and its affinity to the inorganic nanocrystal surface. Anchoring groups, such as thiols, histidines, and amines have been used for ligand exchange.10,40,41,42,44-46 The overall mechanism for interaction and binding between to the nanocrystals is driven by coordination chemistry (i.e., dative not covalent binding). Among these, thiol groups exhibit stronger affinity to several metal and semiconductor surfaces. Thiol-appended ligands have been used by several groups to cap ZnS-overcoated nanocrystals (CdSe—ZnS and others).39-42,47-49 
Studies show that CdSe—ZnS QDs capped with dihydrolopoic acid (DHLA) exhibit much better stability than those cap exchanged with monothiol appended ligands (due to the chelating effect of the bidentate anchoring group), even though long term stability is limited to basic buffer conditions.39 QDs cap exchanged with polyethylene glycol (PEG)- and zwitterion-appended dihydrolipoic acid (DHLA) ligands exhibit enhanced stability over a broad range of biological conditions, such as high electrolyte concentration and over a wide range of pHs.40,48,50 More recently the Michael addition technique was used to append two thioactic acid (TA), or DHLA groups onto the PEG, producing a higher coordination onto Au and QD surfaces, respectively.47 
The bis(TA)-PEG and bis(DHLA)-PEG ligands substantially improved the stability of water dispersions of AuNPs and QDs compared to monothiol- and dithiol-terminated analogues. Nonetheless, further functionalization of those ligands with reactive groups is tedious. These finding clearly indicated that increased coordination of the ligand onto the nanocrystal surface is beneficial.
In this context, some researchers have focused on increasing the coordination to the metal surfaces by grafting a mercaptoethylamine groups onto a short polyacrylic acid (PAA) backbone. In these studies, approximately 15% of the carboxy groups along the PAA backbone were reacted with mercaptoethylamine groups. When QDs were coated with these polymers, coated QDs were dispersible in aqueous media51 because of the availability of several carboxy groups on the nanocrystals.
Using similar concepts, other researchers designed a coating polymer made of a polymethacrylate chain appended with several lateral PEG, namely PEG2000, chains. Some of the PEG chains were terminally functionalized with TA anchoring groups. CdSe—ZnS nanoparticles coated with these coating polymers are dispersible in buffer media.52,53 
Although these coating polymers are water dispersible, improvement is needed.